The perception of pain is a complex process involving central integration of nociceptive sensory signals with autonomic, emotional, motor and behavioural cortical networks. The principal aim of this thesis was to explore how this process contributes to the presenting clinical phenotype in complex regional pain syndrome (CRPS), and whether this extends to other chronic pain conditions in rheumatic disease such as osteoarthritis (OA) and rheumatoid arthrits (RA). The first study established baseline quantitative sensory testing parameters and autonomic function. It found that allodynia was absent in controls, present in some OA and RA patients and most marked in CRPS patients. Autonomic function was normal in controls, with some impairment in OA and RA and most dysfunction in CRPS. The second study used an optokinetic visuo-motor challenge induced by a mirror-whiteboard device. The presence or absence of sensory disturbances and/or new/worsening pain was used to generate a vulnerability scale. Controls were the least vulnerable followed by RA, then OA with CRPS the most vulnerable. Autonomic responses, sensory disturbances and new/worsening pain to a pure visual conflict in the form of ambiguous visual stimuli (AVS) were used for the third study. Sensory disturbances, pain enhancement and abnormal asymmetric autonomic responses occurred only in the CRPS cohort. The final study investigated parietal lobe function in CRPS patients. It showed clinical evidence of parietal lobe dysfunction present in a substantial number of CRPS patients, and that this was reflected both in symptoms and impact upon activities of daily living. Overall, the thesis findings support the concept that perterbation of central somaesthetic integration may induce cortical network dysfunction, reflected in different patterns of autonomic and pain responses. This might contribute to the differing clinical presentations seen in CRPS. Similar processes may also occur in OA and RA. This work provides an approach to the clinical phenotyping of CRPS and other chronic painful rheumatic diseases. Appreciation of the potential mechanisms described may allow better targeting of therapy.

Background: Determinants of response and relapse to B cell depletion in rheumatic diseases is poorly understood, but necessary to improve its clinical use. Objectives: The aims of this study were (1) to test peripheral blood biomarkers for non-response in RA and systemic lupus erythematosus; (2) to evaluate variations in treatment regimen using these biomarkers; (3) to correlate peripheral blood findings with synovial tissue Results: In both RA and SLE, peripheral blood B cell subsets were predictive of response and relapse. Increase numbers of.memory B cells and plasma blasts before or immediately after rituximab were predictive of worse responses, and numbers of these subsets in early repopulation were predictive of relapse. Differences in pattern of depletion and re population were observed between these diseases. These markers correlated with improved response when combining rituximab with alternative DMARDs, when altering rituximab dose, or using early retreatment to improve poor response. Changes in antibodies were studied: these did not correlate with clinical response, but persistently high levels of rheumatoid factor after rituximab were predictive of earlier relapse, as was persistence of synovial plasma cells. Baseline levels of BAFF and IL-6 were predictive of clinical response. Abnormalities ofT cell homeostasis were partially reversed by rituximab, which also correlated with clinical response. Pilot data indicate changes in B cell phenotype in some patients whose importance in clinical response is as yet undetermined. In SLE, some subtypes of disease were less responsive to rituximab. Conclusions: Increased B cell numbers before and after rituximab predict worse clinical response, but this can be overcome by dose, combination DMARD or retreatment interval. Markers of B cell activation prior to rituximab predict good response to treatment. However, after rituximab, these markers, as well as B cell repopulation, also predict earlier relapse and the need for retreatment. These observations provide a rationale for future attempts to improve clinical use of rituximab.

Rheumatology Out-patient clinics throughout the UK. A particular aim was to identify the contribution of Consultant Rheumatologist, Clinical Nurse Specialist and patient by comparing and contrasting physician-led and nurse-led clinics. A total of 107 direct observations from audio recordings of clinic consultations were analysed with the Roter's Interactional Analysis System (RIAS). This produced a patient centeredness score for each consultation as well as classification of interaction as either task focussed or socio-emotional. 'Patient initiated question asking' (not prompted.by the practitioner through questions) was of particular interest but is not distinguished under the RIAS. Hence, 10 cases (patient and practitioner matched consultation transcripts and interviews) were selected for further exploration of patient initiations to offer greater insight into the patients' meaning making. Thirty semi-structured interviews were undertaken with practitioners (N::;16) and patients (N=15) within 24hrs following their consultation and analysed using thematic analysis. The purpose of the analysis was to explore both practitioner and patient perceptions of the clinic visit to inform the interaction analysis undertaken using the RIAS. This research has enhanced understanding of Clinical Nurse Specialist consultations in Rheumatology, in particular the role of communication in the interaction and potential means to enhance patient participation as a precursor to shared clinical decision making. It is concluded that identifying processes of care and communication behaviours that are patient-centred help to activate patients. The contribution of a theoretical framework of Context-Mechanism-Outcome illuminates that processes do not occur in a vacuum and that contextual characteristics are especially important when comparing across practitioner groups .

Musculoskeletal ultrasound (US) is an imaging modality with the potential to revolutionise the way we practise rheumatology. Ultrasound has been shown to be more sensitive and valid when compared to conventional imaging methods and clinical examination in the assessment of inflammatory arthropathies (lA). However, major limitations to its widespread use have been its perceived poor reliability and unknown diagnostic discriminative ability. Image acquisition is a key point for improving reliability. A systematic literature review was performed and a survey of experts was obtained in order to understand the important confounding factors in image acquisition. The effect of two of these factors on synovitis detection was then examined. Non-steroidal anti-inflammatory drugs (NSAIDs) usage was found to significantly mask both grey scale (GS) and power Doppler (PD) signal and resultedinlower assessment of disease activity. Change in the joint position during scanning was found to significantly alter US findings in patients with lA. Scanning the hands in a flat position and the knees in a 30° position provided the highest GS and PD scores suggesting that they may be the optimal scanning positions. The ability of US to discriminate rheumatoid arthritis (RA) from other diseases by detecting bone erosions was explored by examining the specificity of US detected bone erosion. The overall presence of US detected erosions was not a specific fmding for RA. However, erosions in certain anatomical sites were specific for RA. In conclusion, this thesis has demonstrated that certain factors. including concurrent NSAID intake and joint position can affect US image acquisition. Ultrasound does / IV have the ability to discriminate RA from other diseases by specifically detecting bone erosions in target joints. Standardisation of the US confounding factors and better understanding of the specificity of common US findings may enhance the role of US in the assessment of IA.

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The Human Leukocyte Antigen (HLA)-B27 is a Major Histocompability Complex (MHC) class I antigen that is strongly associated with development of a group of closely related arthritic diseases, collectively known as the spondyloarthropathies (SpA). However, the mechanism by which HLA-B27 confers this susceptibility is unclear. Studies have shown that HLA-B27 heavy chains can form classical heterotrimers associated with peptide and β2-microglobulin (B27HT), and also non-classical heavy chain homodimers (B27₂). B27₂ assemble intracellularly during maturation and are also expressed at the cell surface following endosomal recycling of B27HT. A pathogenic role for B27₂ has been proposed in two of the current theories of pathogenesis: the B27 homodimer theory and the B27 misfolding and UPR theory. Yet, determinations of the extent, distribution, and triggers of B27₂ expression, as well as the functional consequences of its receptor interactions in AS pathogenesis, have been hampered by the lack of a specific detection reagent. Therefore, to investigate the role of B27₂ in AS, we generated a novel antibody to B27₂ – HD6 – using phage display technology, which binds to in vitro refolded B27₂ but not B27HT complexes by ELISA. This thesis provides evidence that HD6-reactive molecules, which include B27₂, are expressed at the cell surface in both cell lines and in the context of a disease setting. Recognition is B27-specific and strongly correlated with the magnitude of B27 expression, which could account for the lack of staining in some cell subsets. Moreover, staining was comparable in cell lines expressing the disease-associated B*27:05 and the less disease-associated subtype B*27:09. In addition, I have shown cells expressing physiologic levels of B27, including EBV-transformed BCLs and AS patient PBMCs, are capable of expressing the HD6 epitope upon low pH treatment. Interestingly, these ‘acid-inducible HD6’ molecules were absent from cells lacking a functional PLC. Finally, I have shown that HD6-reactive molecules can derive from pre-existing folding B27 molecules at the cell surface, which may be inhibited by the addition of exogenous B27-binding peptides. These findings are consistent with a mechanism of pathogenesis involving the surface expression and recognition of B27₂ and/or other aberrantly folded forms of B27, as proposed in the homodimer theory. HD6 will be a powerful tool to address the potential pathogenic role of B27₂ in SpA and may additionally have therapeutic potential.